PD-1/PD-L1抑制剂在非小细胞肺癌中的临床研究进展
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摘要
非小细胞肺癌(non-small cell lung cancer, NSCLC)是肺癌最常见的病理类型。近年来,免疫治疗迅速发展,免疫检查点抑制剂尤其是程序性死亡因子-1(programmed death-1, PD-1)/程序性死亡因子配体-1(programmed death-ligand 1, PD-L1)抑制剂已在NSCLC的治疗中取得突破性进展,改变了NSCLC治疗的格局。以PD-1/PD-L1为靶点的免疫检查点抑制剂无论在晚期NSCLC的一线和二线治疗,局部晚期NSCLC的辅助治疗,还是早期NSCLC的新辅助治疗中均为患者带来获益,在NSCLC的综合治疗中显示出重要地位。本文针对以PD-1/PD-L1为靶点的免疫检查点抑制剂在NSCLC中的临床研究进展展开综述。
Non-small cell lung cancer(NSCLC) is the most common pathological type of lung cancer. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors, especially programmed death-1(PD-1)/programmed death-ligand 1(PD-L1) inhibitors have made a breakthrough in the treatment of NSCLC and changed the treatment pattern for NSCLC. Immunological checkpoint inhibitors targeting PD-1/PD-L1 are beneficial to patients, both in the first-line and second-line treatment of advanced NSCLC, in the adjuvant treatment of locally-advanced NSCLC, and in the neoadjuvant therapy of early NSCLC, which show an important role in the comprehensive treatment of NSCLC. This article reviews the clinical research progress of immunological checkpoint inhibitors targeting PD-1/PD-L1 in NSCLC.
Non-small cell lung cancer(NSCLC) is the most common pathological type of lung cancer. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors, especially programmed death-1(PD-1)/programmed death-ligand 1(PD-L1) inhibitors have made a breakthrough in the treatment of NSCLC and changed the treatment pattern for NSCLC. Immunological checkpoint inhibitors targeting PD-1/PD-L1 are beneficial to patients, both in the first-line and second-line treatment of advanced NSCLC, in the adjuvant treatment of locally-advanced NSCLC, and in the neoadjuvant therapy of early NSCLC, which show an important role in the comprehensive treatment of NSCLC. This article reviews the clinical research progress of immunological checkpoint inhibitors targeting PD-1/PD-L1 in NSCLC.
引文
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14 Barlesi F,Vansteenkiste J,Spigel D,et al.Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer(JAVELIN Lung 200):an open-label,randomised,phase 3 study.Lancet Oncol,2018,19(11):1468-1479.doi:10.1016/s1470-2045(18)30673-9
15 Carbone DP,Reck M,Paz-Ares L,et al.First-line nivolumab in stage IVor recurrent non-small-cell lung cancer.N Engl J Med,2017,376(25):2415-2426.doi:10.1056/NEJMoa1613493
16 Reck M,Rodriguez-Abreu D,Robinson AG,et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.NEngl J Med,2016,375(19):1823-1833.doi:10.1056/NEJMoa1606774
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18 Borghaei H,Langer CJ,Gadgeel S,et al.24-month overall survival from KEYNOTE-021 Cohort G:pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous non-small cell lung cancer.J Thorac Oncol,2019,14(1):124-129.doi:10.1016/j.jtho.2018.08.004
19 Gandhi L,Rodríguez-Abreu D,Gadgeel S,et al.Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.N Engl J Med,2018,378(22):2078-2092.doi:10.1056/NEJMoa1801005
20 Paz-Ares L,Luft A,Vicente D,et al.Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer.N Engl J Med,2018,379(21):2040-2051.doi:10.1056/NEJMoa1810865
21 Socinski MA,Jotte RM,Cappuzzo F,et al.Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.N Engl J Med,2018,378(24):2288-2301.doi:10.1056/NEJMoa1716948
22 Hellmann M D,Ciuleanu TE,Pluzansk i A,et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.N Engl J Med,2018,378(22):2093-2104.doi:10.1056/NEJMoa1801946
23 Antonia SJ,Villegas A,Daniel D,et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med,2017,377(20):1919-1929.doi:10.1056/NEJMoa1709937
24 Liu J,Blake SJ,Yong MC,et al.Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease.Cancer Discov,2016,6(12):1382-1399.doi:10.1158/2159-8290.CD-16-0577
25 Puri S,Shafique M,Gray JE.Immune checkpoint inhibitors in earlystage and locally advanced non-small cell lung cancer.Curr Treat Options Oncol,2018,19(8):39.doi:10.1007/s11864-018-0556-7
26 Retseck J,Nasr A,Lin Y,et al.Long term impact of CTLA4 blockade immunotherapy on regulator y and effector immune responses in patients with melanoma.J Transl Med,2018,16(1):184.doi:10.1186/s12967-018-1563-y
27 Forde PM,Chaft JE,Smith KN,et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med,2018,378(21):1976-1986.doi:10.1056/NEJMoa1716078
28 Colli LM,Machiela MJ,Zhang H,et al.Landscape of combination immunotherapy and targeted therapy to improve cancer management.Cancer Res,2017,77(13):3666-3671.doi:10.1158/0 0 08-5472.CAN-16-3338
29 Routy B,Le Chatelier E,Derosa L,et al.Gut microbiome inf luences efficacy of PD-1-based immunotherapy against epithelial tumors.Science,2018,359:91-97.doi:10.1126/science.aan3706
30 Tazda it M,Mezqu ita L,L a h ma r J,et al.Pat ter ns of responses i n metastat ic NSCLC du r i ng PD-1 or PDL-1 i n h ibitor t herapy:Comparison of R ECIST 1.1,irR ECIST and iR ECIST criteria.Eur JCancer,2018,88:38-47.doi:10.1016/j.ejca.2017.10.017
31 Cottrell TR,Thompson ED,Forde PM,et al.Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma:a proposal for quantitative immune-related pathologic response criteria(irPRC).Ann Oncol,2018,29(8):1853-1860.doi:10.1093/annonc/mdy218
32 Sharma P,Hu-Lieskovan S,Wargo JA,et al.Primary,adaptive,and acquired resistance to cancer immunotherapy.Cell,2017,168(4):707-723.doi:10.1016/j.cell.2017.01.017
33 Hanahan D,Coussens LM.Accessories to the crime:functions of cells recruited to the tumor microenvironment.Cancer Cell,2012,21(3):309-322.doi:10.1016/j.ccr.2012.02.022
2 Goldstraw P,Chansky K,Crowley J,et al.The IASLC Lung Cancer Staging Project:Proposals for Revision of the TNM Stage Groupings in the Forthcoming(Eighth)Edition of the T NM Classif ication for Lung Cancer.J Thorac Oncol,2016,11(1):39-51.doi:10.1016/j.jtho.2015.09.009
3 Francisco LM,Sage PT,Sharpe AH.The PD-1 pathway in tolerance and autoimmunity.Immunol Rev,2010,236:219-242.doi:10.1111/j.1600-065X.2010.00923.x
4 Keir ME,Butte MJ,Freeman GJ,et al.PD-1 and its ligands in tolerance and immunity.Ann Rev Immunol,2008,26:677-704.doi:10.1146/annurev.immunol.26.021607.090331
5 Keir M E,Liang SC,Guleria I,et al.Tissue ex pression of PD-L1mediates peripheral T cell tolerance.J Exp Med,2006,203(4):883-895.doi:10.1084/jem.20051776
6 Pa rdol l DM.T he bloc k a de of i m mu ne c he c k poi nt s i n c a nc er immunotherapy.Nat Rev Cancer,2012,12(4):252-264.doi:10.1038/nrc3239
7 Brahmer J,Reckamp KL,Baas P,et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med,2015,373(2):123-135.doi:10.1056/NEJMoa1504627
8 Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med,2015,373(17):1627-1639.doi:10.1056/NEJMoa1507643
9 Vokes EE,Ready N,Felip E,et al.Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer(CheckMate017 and Check Mate 057):3-year update and outcomes in patients with liver metastases.Ann Oncol,2018,29(4):959-965.doi:10.1093/annonc/mdy041
10 Gettinger S,Horn L,Jackman D,et al.Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer:results from the CA 209-003 study.J Clin Oncol,2018,36(17):1675-1684.doi:10.1200/JCO.2017.77.0412
11 Herbst RS,Baas P,Kim DW,et al.Pembrolizumab versus docetaxel for previously treated,PD-L1-positive,advanced non-small-cell lung cancer(KEYNOTE-010):a randomised controlled trial.The Lancet,2016,387(10027):1540-1550.doi:10.1016/s0140-6736(15)01281-7
12 Fehrenbacher L,Spira A,Ballinger M,et al.Atezolizumab versus doceta xel for patients with previously treated non-small-cell lung cancer(POPLA R):a multicentre,open-label,phase 2 randomised controlled trial.Lancet,2016,387(10030):1837-1846.doi:10.1016/s0140-6736(16)00587-0
13 R ittmeyer A,Barlesi F,Waterkamp D,et al.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer(OA K):a phase 3,open-label,multicentre randomised controlled t r ia l.L a ncet,2 017,389(10 0 6 6):255-2 65.doi:10.1016/s 014 0-6736(16)32517-x
14 Barlesi F,Vansteenkiste J,Spigel D,et al.Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer(JAVELIN Lung 200):an open-label,randomised,phase 3 study.Lancet Oncol,2018,19(11):1468-1479.doi:10.1016/s1470-2045(18)30673-9
15 Carbone DP,Reck M,Paz-Ares L,et al.First-line nivolumab in stage IVor recurrent non-small-cell lung cancer.N Engl J Med,2017,376(25):2415-2426.doi:10.1056/NEJMoa1613493
16 Reck M,Rodriguez-Abreu D,Robinson AG,et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.NEngl J Med,2016,375(19):1823-1833.doi:10.1056/NEJMoa1606774
17 De Lima Lopes G,Wu YL,Sadowski S,et al.P2.43:Pembrolizumab vs plat i nu m-based chemot herapy for PD-L1+NSCLC:phase 3,randomized,open-label K EYNOTE-042(NCT02220894).J Thorac Oncol,2016,11(10):S244-S245.doi:10.1016/j.Jth.2016.08.114
18 Borghaei H,Langer CJ,Gadgeel S,et al.24-month overall survival from KEYNOTE-021 Cohort G:pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous non-small cell lung cancer.J Thorac Oncol,2019,14(1):124-129.doi:10.1016/j.jtho.2018.08.004
19 Gandhi L,Rodríguez-Abreu D,Gadgeel S,et al.Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.N Engl J Med,2018,378(22):2078-2092.doi:10.1056/NEJMoa1801005
20 Paz-Ares L,Luft A,Vicente D,et al.Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer.N Engl J Med,2018,379(21):2040-2051.doi:10.1056/NEJMoa1810865
21 Socinski MA,Jotte RM,Cappuzzo F,et al.Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.N Engl J Med,2018,378(24):2288-2301.doi:10.1056/NEJMoa1716948
22 Hellmann M D,Ciuleanu TE,Pluzansk i A,et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.N Engl J Med,2018,378(22):2093-2104.doi:10.1056/NEJMoa1801946
23 Antonia SJ,Villegas A,Daniel D,et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med,2017,377(20):1919-1929.doi:10.1056/NEJMoa1709937
24 Liu J,Blake SJ,Yong MC,et al.Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease.Cancer Discov,2016,6(12):1382-1399.doi:10.1158/2159-8290.CD-16-0577
25 Puri S,Shafique M,Gray JE.Immune checkpoint inhibitors in earlystage and locally advanced non-small cell lung cancer.Curr Treat Options Oncol,2018,19(8):39.doi:10.1007/s11864-018-0556-7
26 Retseck J,Nasr A,Lin Y,et al.Long term impact of CTLA4 blockade immunotherapy on regulator y and effector immune responses in patients with melanoma.J Transl Med,2018,16(1):184.doi:10.1186/s12967-018-1563-y
27 Forde PM,Chaft JE,Smith KN,et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med,2018,378(21):1976-1986.doi:10.1056/NEJMoa1716078
28 Colli LM,Machiela MJ,Zhang H,et al.Landscape of combination immunotherapy and targeted therapy to improve cancer management.Cancer Res,2017,77(13):3666-3671.doi:10.1158/0 0 08-5472.CAN-16-3338
29 Routy B,Le Chatelier E,Derosa L,et al.Gut microbiome inf luences efficacy of PD-1-based immunotherapy against epithelial tumors.Science,2018,359:91-97.doi:10.1126/science.aan3706
30 Tazda it M,Mezqu ita L,L a h ma r J,et al.Pat ter ns of responses i n metastat ic NSCLC du r i ng PD-1 or PDL-1 i n h ibitor t herapy:Comparison of R ECIST 1.1,irR ECIST and iR ECIST criteria.Eur JCancer,2018,88:38-47.doi:10.1016/j.ejca.2017.10.017
31 Cottrell TR,Thompson ED,Forde PM,et al.Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma:a proposal for quantitative immune-related pathologic response criteria(irPRC).Ann Oncol,2018,29(8):1853-1860.doi:10.1093/annonc/mdy218
32 Sharma P,Hu-Lieskovan S,Wargo JA,et al.Primary,adaptive,and acquired resistance to cancer immunotherapy.Cell,2017,168(4):707-723.doi:10.1016/j.cell.2017.01.017
33 Hanahan D,Coussens LM.Accessories to the crime:functions of cells recruited to the tumor microenvironment.Cancer Cell,2012,21(3):309-322.doi:10.1016/j.ccr.2012.02.022